Note: Descriptions are shown in the official language in which they were submitted.
~ 37174
The present invention relates to novel tetracyclic
cGmpounds, and to their proauction and use.
The t~tracyclic compounds of this invention can be
represent~d by the formula:
CH2~N [I]
\ 2
. \
wherein Rl is hydrogen or Cl-C3 alkyl, R2is Cl-C3 alkyl, yl
is hydrogen or halogen and X1 is a divalent radical selected
from the group consisting of -O-, -S-, -N(R3)- and -CO-, R3
being hydrogen or Cl-C3 alkyl, and the pharmaceutically
acceptahle salts thereof.
In the above , the term "Cl-C3 alk~yl"
ncludes methyl, ethyl and isopropyl, ancl the term
"halogen" covers fluorine, chlorine and bromine.
The tetracyclic compounds [I] may form acid addi-
~ion salts (e.g. hydrochloride, hydrobromide, sulfate,
acetate, oxalate, citrate, f~arate, maleate, lactate,
tartrate) and quaternary ammonium salts (e.g. methochloride,
methiodide).
The tetracyclic compounds [I~ and the pharmaceutically
acceptable salts thereof exhibit various ph2rmacological
activities and are thus useful as medicines. In general, they
affect the functioning or the central n~rvous syste~. That
is, they antagonize the central nerVous system depressaIIt
effect induced by tetrabenazine and by reserpine, and also
potentiate the central action of norepinephrine. Therefore,
the co~lpounds and their salts are useful as antidepressants.
-- 2 --
, .
. ~
1~37174
- ~mong the tetracyclic com~ounds lI] of the inven-
tion, those having the following formula are preferable:
( _ ~ ~ R4
wherein R4 is hydrogen or methyl, and Xl and yl are each as
defined above, and the pharmaceutically acceptable salts
thereof.
The compounds of the fo].lowi.n~ formula are
particularly preferable:
2 \ ~I"] ~ :~
CH3
~1 . .
wherein x2 is a divalent radical selected from the group
consisting of -O-, -NH-, -N(CH3)- and -CO-, and R and Y
are each as defined above, and the pharmaceutically accept-
able salts thereof.
~ he compounds of the follow.ing formula ar2 the most
preferable:
' ~ [I"']
~-~ CH3
\y~
wherein y2 is hydrogell or chlorine, and R4 and x2 are each
as defined a~)ove, and the pharmaceutically acceptable salts
-- 3 --
10~37174
thereof.
The tetracyclic compounds [I] and the pharma-
ceutically acce~table salts thereof can be administered
parenterally or orally with dosages adjusted to individual
requirem~nts (10 - 300 mg/hurnan body ~i.e. a body ~eight of 60
kg]/day) in the form of conventional pharmaceutical prepara-
tions. For instancc, they may be administered in the form
of a conventional solid pharmaceutical preparation,such as
tablets or capsules,or in the form of a conventional liquid
pharmaceutical preparation,such as suspensions, emulsions or
solutions.
The tetracyclic compounds [I] can be prepared by
various methods according to the invention, as
follows:
(a) The tetracyclic compound of the formula:
CH2 N \ 2 [Ial
R
yl
wherein X3 is a divaient radical selected from the group
co~sisting of -O-, -S- and -N(R3)-, and Rl, R2, R3 ~n~ yl
are each as defined above,can be prepared by reduction of
the corresponding amide of the formula:
~C-N I I I ]
~\ \R2
, ~yl
wherein R , R , R , X and Y are each as defined above.
- 4 -
~_ . . ...... .... , .. _
- , . .
37174
The reduction may be carried out by the use of any
reducing agent conventionally employed for the reduction of ~ -
an amide to an amine. One of the most preferred reducing
agents is a metal hydride such as lithium aluminum hydride,
sodium bis(2-methoxyethoxy)aluminum hydride or sodium
dihydrodiethyl aluminate. The reducing agent can be used
in an equimolar amount to the amide [II], or in an excess. r
When sodium borohydride is used as the reducing
agent, the presence of a salt such as aluminum chloride is
10 desirable. ~hen desired, an inert solvent such as an ether
(e.g. diethyl ether, tetrahydrofuran, dioxane, ethylene
glycol dimethyl ether), an aliphatic hydrocarbon (e.g. n- -
hexane n-heptane, cyclohexane) or an aromatic hydrocarbon
(e.g. benzene, toluene), may be employed in the reduction.
The temperature employed during the.reduction can be any
temperature from the ice-cooling temperature to the refluxing
temperature of the reduction system.
(b) The tetracyclic compound of the formula:
H ~ `C~I2 N lIb]
`yl
wherein Rl, R2 and yl are each as defined above can be
prepared by hydrcgenolysis or by hydrogenolysis and reduc-
tion of the corresponding compound of the formula:
7j Rl
\ R? [III]
-- 5 --
101!37174
wherein ~ is Cl-C3 alkyl or cl-c3 al~oxy and z is an oxygen
or two hydrouens, and Rl, R2 and yl are each as defined
above.
The hydrogenolysis and reduction may be carri~d
out by using a metal hydride,such as lithium aluminum
hydride, lithium aluminum diethoxyhydride or lithium
aluminum trietho~yllydride, preferably in the presence of an
inert solvent,such as an ether ~e.g. diethyl ether, tetra-
hydrofuran, dio~ane, ethylene glycol dime.hyl ether), an
aliphatic hydrocarbon (e.g. n-hexane, n-heptane, cyclo-
hexane) or an aromatic hydrocarbon (e.g. benzene, toluene).
The temuerature employed for the hydro~-enolysis and reduction
~` can be any temperature from the ice-cooliny tem~era~ure to the
: .
refluxing temperature of the reaction system.
(c) The tetracyclic compounds of the formula:
.. ; ~
o=C ~ CH2-N~ ~Ic]
>=\ \ R2
,,. ~1 .
wherein Rl, R2 and yl are each as defined above can be
prepared by oxidation of the corresponding alcohol of the
formula: -
'' f~\
Rl
~--~
HO~ C112-N \ R2 [IV] ~
yl ::
wherein 1~l, R2 and yl are each as defined above.
; The oxidation may be accomplish~d by the use of an
'
~ o ~
. .
. . .
~ ~ .
.
. .
- - . .... .
87174
oxidiziny agcllt conventionally e~ployed for the oxi-
dation of an alcohol to a ketone. Preferred o~:idizing
agents are mangancse dioxide, chromic acid, chromates and so
on. The oxida'ion reaction is ordinarily carried out in an
inert solvent,such as an aliphatic hydrocarbon (e.g. n-
hexane, n-pentane), a chlcrinated aliphatic hydrocarbon
(e.g. dichloromethane, chloroform, carbon tetrachloride), an
aromatic hydrocarbon (e.g. benzene, toluene), a carboxylic
acid (e.g. acetic acid) or a ketone (e.g. acetone, ~ethyl
ethyl ketone). The temperature for the reaction can be
varied from ice-cooling to the refluxing temperature of the
reaction system.
(d) The tetracyclic compound of the formula:
CH / [Id]
.
\yl
wherein X4 is a divalent radical selected from the group
consisting of -n-, -s-, -N(Cl-C3 alkyl)- and -CO-, and Rl,`
R2 and yl are each as defined above can be p~epared by the
reaction of the corresponding compound of the formula:
~4 ~ C [V]
wherein W i~ a conventional"leaving group"selecte~d from the
group consisting of halogen (e.g. chlorine, bromine) or
- 7 -
_' ' -- _~
..
37174
sulfonyloxy (e.g. methanesulfonylo~y, p-toluenesulfonyloxy),
and X4 and yl are each as de~ined ~bove, with ar. amine of
the formula:
Rl
H-N EVI]
\R2
wherein Rl and R2 are each as defined above in an inert
organic solvent such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, ethylene glycol dimethyl ether,
ethanol, methanol, benzene, toluene or pyrldine in the
presence or absence of an acid binding agent. Examples of
the acid binding agent are pyridine, pico].ine, triethyl-
ami.ne, di.methylaniline, etc. The temperature employed for
the reaction may be any temperature from the ice-cooling tem-
perature to the refluxing- temperature of the reaction system.
(e) The tetracyclic compound of the formula:
~R6
R -N ~ ~ CH2-N [Ie]
\yl
wherein R6 and R7 are each Cl-C3 alkyl, and R2 and yl are
each as defined above can be prepared by the condensation of
the corres~onding compounc of the formula:
~--) / R
H ~ ~ CH2-~ VII]
\yl
wherein R2, R6 alld yl are each as defined above with an
alkylating agent of the formula:
.
- 8 -
.,
10~37174
; W-R7 tVIII]
wherein R7 and W are each as defined above, in the presence
of an acid binding agent such as sodium hydride or sodium
amide in an inert solvent such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl
: ether, benzene or toluene. The temperature er.~loyed for the
condensation may be any temperature from the ice-cooling tem-
pexature to the refluxing terllperature of the reaction syste~.
The thus prepared tetracyclic compounds [I] can be
converted into their salts by any conventional procedure, and
reconversion from the salts to the original free bases
can be also carried out in a conventional manner.
Various starting materials in the above methods
are novel and can be produced according to the following
scheme:
. .
.,
.
." . .
:. :
_ g _
.. : . : ,
'
1~37174
; X~5 ~ <~ ~ C02R8
\yl / yl
IIX] / ~Xl
--CH 20H ~ CON
yl~ \ yl
[XIII] / IXI] I
f ~
-CH2-W HN~--CON HO-CH ,~>-C112-N
\yl yl \yl
:~ [V] [XII] [IV]
wherein X5 is a divalent radical selected Erom the group
: consisting of -O-, -S-, -N(Cl-C3 alkyl)-, -NCoR5- and -CO-, x6
is a divalent radical selected from the group consisting of
- -o-, -S-, -N(R )- and -CHOH-, R is Cl-C3 alkyl, and ~ , R , R ,
:~ :
137174
~: .
X4, yl and W are each as d~fined abov~.
That is, the tricyclic compounds [IX~ are reacted
with alkoxycarbonyl carbenes, prepared from alkyl diazo-
acetates, to afford the alkyl cyclopropanecarboxylates lX].
The carboxylates [X] are saponified to the corresponding
carboxylic acids, which are then converted into their active
derivatives such as acid anhydrides or acid halides and
reacted with amines to afford the tetracyclic amides [XI].
Further, the amides [XI] wherein X5 is -~CoR5- may be
10 reacted with metal hydride complexes such as lithium aluminum
hydride at lower temperatures to afford the amides [XIIl, or
the amides [XI] wherein X5 is -CO- are reduced to the amines
c [IV]. Alternatively, the carboxylates lX] may be reduced to
I the corresponding alcohols [XIII], followed by active ester-
ification to afford the compounds lV]. The compound [XIII] - -
wherein x6 is -CHOH- may be oxidized to the corresponding
ketones, followed by active esterification to afford the
compounds [V] wherein X4 is -CO-.
Some of the tricyclic compounds [IX] and their methods
20 of preparation are known, and the other compounds may be derived
. ~
therefrom according to per se conventional procedures or -~
synthesized in the similar manner thereto.
~or instance, dibenz[b,f]oxepin [IX: X5 = O; yl 3
H] and its 2-chloro derivative [IX X5 a o; yl = Cl] [V~
Seidlova et al.: Coll. Czech. Chem. Collm., 34, 2258
(1969)], dibenzolb,f]thiepin [IX: X5 = S; yl = H] EJ.o.
Jilek et al.: M~natsch. Chem., 96, 182 (1965)], dibenzo-
[b,f]tropone [IX: X5 = CO; yl = H] [W. Treibs et al.:
Chem. Ber., 84, 671 (1951)] and its 2-ch1oro derivative [IX:
30 X = CO; yl = Cl] [C.A. Stone et al.: J. Med. Chem., 8, 829
1087174
(1965)], SH-dibenz[b,f]azepine [IX: X5 = NH; Y = H] [L.J
Kricka et al.: J.C.S. Perkin I, 2292 (1972)] and its 2- i
fluoro derivati~e [IX: X5 = NH; yl = F] and 2-chloro deri-
vative [IX: X5 = NH; yl = Cl] [R.S. Varma et al.: J. Med.
Chem., 12, 913 (1969)], etc. are known. 2-Fluorodibenz[b,f]-
oxepin [IX: X5 = O; yl = F], 2-bromodibenz[b,f]oxepin [IX:
X5 = O; yl = Br], 2-fluorodibenz[b,f]thiepin [IX: X5 = S;
yl = F], 2-chlorodibenz[b,f]thiepin [IX: X5 = S; yl = Cl]
and 2-bromodibenzlb,f]thiepin [IX: X5 = S; yl = Br] may be
produced in the same manner as described in the said V.
Seidlov~ et al. literature or the said J.O. Jilek et al.
literature. 2-Fluorodibenzo[b,f]tropone [IX: X5 = CO; yl =
F~ and 2-bromodibenzo[b,f]tropone [IX: X5 = CO; yl = Br]
may be produced by the same method as described in the said -~
C.A. Stone et al. literature. 2-Bromo-5H-dibenz[b,f]azepine
may be produced in the same procedure 2S disclosed in the
said R.S. Varma et al. literature.
Further, methylation of 5H-dibenz[b,f]azepine by a
per se conventional proceudre affords 5-methyl-5H-dibenz-
[b,f]azepine [IX: XS = N(CH3); yl = H] (M.P. 130 -131C).
Likewise, acylation of 5H-dibenz[b,f]azepine with an acetylat-
ing agent or a carbethoxylating agent can afford respec-
tively S-acetyl-5H-dibenz[b,f]azepine [IX: X = N(COCH3);
Y = H] (M.P. 121 - 122C) and 5-carbethoxy-SH-dibenz[b,f]-
azepine [IX: X = N(COOC2H5); yl = H] (M.P. 142 - 144C).
Examples of the compounds which are producible by alkylation
or acylation of 2-fluoro-5H-dibenz[b,f]azepine, 2-chloro-SH-
dibenz[b,f]azepine or 2-bromo-SH-dikenz[b,f]azepine are as
follows: 2-fluoro-5-(Cl-C3)alkyl-5H-dibenz[b,f]azepine [IX:
X5 = N(Cl-C3 alkyl); yl = F], 2-fluoro-5-(C2-C4)alkanoyl-5H-
- 12 -
.
. . .
10i37~74
dibenz[b,f]azepine ~IX: X5 = NCO(Cl-C3 alkyl); Y = F], 2-
fluoro-5-(~2-C4)carbalkoxy-5H-dibenz[b,f]azepine [IX: X5 =
NCOO(Cl-C alkyl); yl = F], 2-chloro-5-(Cl-C3)alkyl-5H-
dibenz[b,f]azepine [IX: X5 = N(Cl-C3)alkyl; yl = Cl], 2-
chloro-5-(C2-C4)alkanoyl-51l-dibenz[b,flazepine [IX: X5 =
NCO(Cl-C3 alkyl); yl = Cl], 2-chloro-5-(C2-C4)carba]koxy-5~1-
dibenz[b,f]azepine [IX: X5 = NCOO(Cl-C3 alkyl); yl = Cl],
2-bromo-5-(cl-c3)al!~yl-5~l-dibenz[b~f]a~epine [IX: X5 =
N(Cl-C3)alkyl; yl = Br], 2-bromo-5-(C2-C4)al~anoyl-5El-
dibenz[b,f]azepine [IX: X5 = NCO(Cl-C3 alkyl); yl = Br], 2-
bromo-5-(C2-C~)carbalkoxy-5~-dibenz[b,f]azepine [IX: X5 =
NCOO(Cl-C3 alkyl); yl = sr], etc.
The following Examples are given for the purpose
of illustration only, and it is not intended to limit the
scope of thP invention thereto.
Example 1
. .
A solution of l-(N,N-dimethyl-carbamoyl)-3-chloro-
1,la,6,10b-tetrahydrodebenzo [b,f]-cyclopropa[d]oxepin
(2.10 g) in tetrahydrofuran (20 ml) was added to a solution
20 of llthium aluminum hydride (1.25 g) in ether (20 ml)
under ice-cooling, and the resulting mixture was stirred for
3 hours at room ~emperature. Water was added to the cooled
reaction mixture in order to decompose excess lithium
; aluminum hydride. The reaction mixture was dried over
sodium sul~ate and filtered. The filtrate ~YaS evaporated
and chromatographed to afford l-tN,~-dimethylaminomcthyl)-3-
; chloro-l,la,6,10b-tetrahydrodibenzo[b,fjcyclopropa[d]oxepin
as an oily substance. M.P. 243 - 244C (hydrochloride).
Exdmple 2
A solution of l-(N-methyl-carbamoyl)-6-ethoxycarbonyl-
~ 37174
l~la~6~lob-tetrahydrodibenzo-~b~f]cyclopropa[d]azepine
(0.67 g) in tetrahydrofuran (40 ml) was added to a solu-
tion of lithium aluminum hydride (0.45 g) in ether (10 ml)
under ice-cooling, and the resulting mixture was stirred
for 6 hours at room temperature and then refluxed for 6
hours. ~ater was added to the cooled reaction mi~ture in
order to decompose excess lithium aluminum hydride. The
reaction mixture was dried over sodium sulfate and filtered.
The filtrate was evaporated and chromatographed to afford 1-
(N-methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo[b,f]-
cyclopropa[d]azepine as crystalline materials. ~I.P. 104 - -~ -
107C.
Example 3
- . _
A mixture of l-(N,N-dimethylaminomethyl)-6-
hydroxy-l,la,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]-
cycloheptdne (0.25 g) in chloroform (20 ml) and mnqanese
dioxide (2.7 g) was stirred at 5~C for 1.5 hours and then at
room temperature for 4 hours. ~fter filtration of inorganic
materials, the filtrate was evaporated and chro;natosraphed
to afford 1-(N,N-dimethylaminomethyl)-l,la,6,10b-tetra-
hydrodibenzo[a,e]cyclopropa[c]cycloheptan-6-one as crystalline
materials. M.P. 78 - 79C.
Example 4
A solution of 1-chloromethyl-6-methyl-l,la,6,10b-
tetrahydrodibenzo~b,f]cyclopropa[d]azepine (0.35 g) in
ethanol (5 ml) was added at room temperature to a solution --
of diisopropylamine (0.30 g) in ethanol (5 ml)~ and stirring
was carried out under reflux for 7 hours. The reaction
mixture was evaporated and poured in~o 10 ~ a~u~ous solutiGn
of sodium hydroxide. The chloroform ~xtract was dried and
.
- 14 -
,:
` ! 1t)~37174
chromatographed to afford l-(N,N-diisopropylaminomethyl)-
6-methyl-l,la,6,10b-tetrahydrodibenzo[b,f~cyclopropa[d]-
azepine as an oily material. M.P. 233 - 235C
(hydrochloride).
Example 5
Sodium amide (60 mg) was added at room temperature
to a solution of l-(N,N-dimethylaminomethyl)-l,la,6,10b-
tetrahydrodibenzo[b,f]cyclopropa[d~azepine (0.25 9) in
tetrahydrofuran (10 ml), and the resulting mixture was
heated under reflux for 1 hour. After cooling, a solu-
tion of methyl iodide (0.25 9) in tetrahydrofuran (1 ml)
was added to the mixture under ice-cooling, and then the
mixture was heated under reflux for 1 hour. After cooling,
water was added thereto, and inorganic materials were
eliminated by filtration. The filtrate was evaporated and
' chromatographed to afford l-(N,N-dimethylaminomethyl)-
; 6-methyl-l,la,6,10b-tetrahydrodibenzo[b,f]cyclopropa[d]-
azepine as crystalline materials. M.P. 93 - 94C;
279 - 280C (hydrochloride).
The following compounds were produced by one or more
of the procedures above:
;- l-(N,N-Dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-
benzo[b,f]cyclopropa[d]oxepin, M.P. 243 - 244C (hydro-
chloride), (by the methods of Example 1 and Example 4);
l-(N-Methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo-
[b,f]cyclopropa[d]oxepin, M.P. 234 - 235C (hydrochloride),
(by the methods of Example 1 and Example 4);
;~ l-(N,N-Diisopropylaminomethyl)-l,la,6,10b-tetrahydro-
dibenzo[b,f]cyclopropa[d]oxepin, M.P. 172 - 174C (hydro-
chloride), (by the methods of Example 1 and Example 4);
l-(N,N-Dimethylaminomethyl)-3-chloro-l,la,6,10b-tetra-
hydrodibenzo[b,f]cyclopropa[d]oxepin, M.P. 243 - 244C
- 15 -
1~87174
(hydrochloride), (by the methods of Example 1 and
Example 4);
l-(N-Methylaminomethyl)-3-chloro-l,la,6,10b-tetrahydro-
dibenzo[b,f]cyclopropa[dloxepin, M.P. 245 - 247C (hydro-
chloride), (by the methods of Example 1 and Example 4);
l-(N,N-Diisopropylaminomethyl)-3-chloro-l,la,6,10b- :
tetrahydrodibenzo]b,flcyclopropa[dloxepin, I.R. tneat):
2950, 1600, 1485, 1260, 1230, 1180, 1110, 835, 770 cm~
(by the methods of Example 1 and Example 4);
1-(N,N-Dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-
benzo[b,flcyclopropa[d]thiepin, M.P. 112 - 114C, (by the
methods of Example 1 and Example 4);
l-(N-Methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo-
[b,f]cyclopropaldlthiepin~ M.P. 238 - 239C (hydro-
chloride), (by the methods of Example 1 and Example 4); -
l-(N,N-Diisopropylaminomethyl)-l,la,6,10b-tetrahydro- :
dibenzolb,f]cyclopropa[d]thiepin, I.R. (neat): 3050,
2950, 1590, 1565, 1470, 1205, 755 cm 1, (by the methods
of Example 1 and Example 4);
1-(N,N-Dimethylaminomethyl)-6-methyl-l,la,6,10b-tetra-
` hydrodibenzo]b,f]cyclopropaEd]azepine, M.P. 93 - 94~C, (by
the methods of Example 1, Example 4 and Example S);
l-(N,N-Dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-
~: benzo[b,flcyclopropald]azepine, M.P. 128 - 129C, (by the
methods of Example 1 and Example 2);
l-(N-Methylaminomethyl)-6-methyl-l,la,6,10b-tetra-
hydrodibenzo[b,f]cyclopropa[d]azepine, M.P. 202 - 207C
.~ (hydrochloride), (by the methods of Example 1 and
-~ Example 4);
1-(N-Methylaminomethyl)-l,la,6,10b-tetrahydrodibenzo-
[b,f]cyclopropa[d]azepine, M.P. 104 - 107C, (by the
.
- 16 -
~ 10~,7174
. .
methods of Example 1 and Example 2);
l-(N,N-Diisopropylaminomethyl)-6-methyl-l,la,6,10b-
tetrahydrodibenzo[b,f]cyclopropa[d]azepine, M.P. 233 - -~
235C (hydrochloride), (by the methods of Example 1,
Example 4 and Example 5);
l-(N,N-dimethylaminomethyl)-l,la,6,10b-tetrahydrodi-
~ benzo[a,e]cyclopropa[c]cycloheptan-6-one, M.P. 78 - 79C,
(by the methods of Example 3 and Example 4).
. .
;
- 16a -
